Di (aminoarylsulphon) amides and a method of making the same



Patented a. is, 1938 UNITED s'r rss DI(AMINOARYL8ULPHON)AMIDES AND A METHOD OF MAKING THE SAME Elmore Hathaway Northey, Bound Brook, N. 1., assignor to The Calco-Chemical Company, Inc., Bound Brook, N. 1., a corporation of Delaware No Drawing.

'13 Claims.

This invention relates to di(aminoarylsulphon) amides and methods of preparing them. Monosulphonamides of aromatic compounds havebeen prepared and some of them have achieved great practical importance as bacteriostats. Notably, the p-aminobenzenesulphonamide, (sulphanilamide), is widely used as a chemotherapeutic against streptococci, gonococci and similar bacteria. 10 also been used as intermediates for'the production of azo dyes. A serious disadvantage of the commercially exploited monoaminosulphonamides, such as sulphanilamide, has lain in their relatively high toxicity. As a result, the difierence between the minimum efiective dose against such organisms as streptococci and the dose which produces serious results or even deathis narrower than is desirable and a number of serious secondary toxic reactions have occurred. The present invention is directed to aminodisulphonamides, many of which possess the important property of increased therapeutic effectiveness against bacteria withoutv increased toxicity and generally with decreased toxicity. The compounds are therefore more useful as therapeutic agents because the greater difference between the eifective dose and fatal dose renders their use much safer in practice.

The present invention is limited to di(amino-* arylsulphon) amides and, in general, covers compounds having the following general formula:

n-sol \NX rv-s. where R is an aminoaryl containing an amino or substituted amino group, R is an aminoaryl and X is hydrogen, a metal or an I or aryl radical.

While the invention is not limited to di(amino-- .arylsulphon) amides, this class is the preferred 7 one and corresponds to-the formula given above where both R and R are aminoaryl groups.

This preferred class includes some of the most effective therapeutic agents covered by the present invention. Most of the cheaper compounds belong to the benzene and naphthalene series but the invention is not limitedto monoand dinuclear compounds andQon the contrary, includes triand other poly-nuclear compounds such as those of the anthracene, phenanthrene, fluorene and similar series.

The position of the amino group on the radical R in the formula given above may vary and in its broader aspects the invention includes compounds inwhich the amino group is ortho, meta or para to the S02 group-in the case of mononuclear compounds and in the alpha or beta positions in the case of naphthalene compounds. In

the case of aliphatic compounds, the group may The monosulphonamides have Application January 1l,'-193 8, Serial No. 184,415

(or zen-44's) be situated at an slut in the chain. For therapcutic purposes, the compounds in which the amino group is para to the SO: group are usually preferable and constltute'a preferred species. In the case of azo dye intermediates, other positions 5 of the amino group are frequently preferable.

For the purpose for which the compounds of. the present invention are particularly useful, it is, usually desirable, although not essential, that they be soluble and therefore compounds in which X V1 in the formula above given is an alkali metal, magnesium, calcium or other base yielding soluble products are preferable. v

For many purposes high solubility is not necessary and salts of other bases may be used which 15 are insoluble or only sparingly soluble. Such bases include heavy metals such as silver, gold, mercury. bismuth, antimony, lead, aluminum, iron and arsenic compounds which are capable of forming salts. Other insoluble compounds in- 20 clude the alkyl and aryl compounds in which alkyl or aryl replaces the remaining hydrogen'of the amino group. The possibility of preparing salts of heavy metals and similar compounds is of great importance therapeutically as many of these 25 metals exert powerful actions against bacteria and other disease-producing organisms. Such compounds where the bacteriostatic action of the diaminoarylsulphonamidesis reenforced or supplemented with therapeutically active metals metal compounds such as for example arsenicals greatly increase the field of utility of the compounds of the present invention.

For therapeutic use, it is usually desirable to provide a substantially neutral medium; accord ingly, the salts are preferable to the acids 'for this purpose. However, for other uses such as azo dye intermediates, the compounds may be present in the form of their acids. that is tos'ay where X is hydrogen, and the present invention is there fore in no sense restricted to salts.

The compounds of the present invention are new chemical compounds and are .claimed as such, regardless of the method by which they have been prepared. I have found, however, tha t good yields of products of high purity may. be obtained, particularly in the case of the di(aminodiarylsulphon) amides, by bringing about reaction between an acylaminoarylsulphonchloride and ammonia or a monosulphonamide. This process is there- 50 fore also covered as a specific feature of the present invention. I

The invention will be described in greater detail in conjunction with the following specific examples which describe the production of typical 55 compounds falling under the present invention. The invention is, however, not limitedto the details therein set forth. Unless otherwise expressed, parts are by weight and parts of water are by corresponding volume.

Exams: 1 Di(N-acetillsulphanil) amide cmoonnos om=Nn 1 mol. of anmionia is dissolved in 150 parts of water at 10 C. and 2 mols of freshly prepared N-acetylsulphanilylchloride paste are gradually added with vigorous agitation. Sufllcient caustic soda solution is added to maintain a pH between 10 and 11.5 and ice is introduced from time to time to keep the temperature between 32and 37 C. After all of the N-acetylsulphanilylchloride has beenadded and the pH has been finally adjusted by means of caustic soda, stirring is continued for about one hour.

The reaction mixture is cooled to 10 C. and solid matter filtered oil. The precipitate constitutes crude sodium di(N-acetylsulphanil) amide. It is purified by recrystallization from hot water atures above 300' C. On diarotisation with nitrous acid, a tetrazo compound is obtained which may be coupledwith the usual coupling components to form azo dyestuifs.

Salts other than the sodium salt may be made inthe case of some of the stronger bases by reaction of a carbonate or hydroxide of the base with disulphanilamide and in other cases, by

double decomposition in aqueous solution of the sodium salt of disulphanilamide with a suitable salt of the metal.

The following table gives a number of representative salts and their method of preparation and properties. The abbreviation Dsa. is used for disulphanilamide and Sod. for sodium. In' referring to the solubility, s. is used for soluble,' v. for very, sl. for slightly, mod. for moderately and ext. for extremely. In the table under method of preparation. the reaction takes place in aqueous solution except where specifically noted.

Salts or duuipnanamue flolnbili i Bait Method of preparation appearance Hot water Gold at.

Lithium Dsa.+LiO0r small white fiat rods or plateau... V. I. V. I. Magnesium. White plates V. I. lied. I. Calciumor Ext. I. V. I. Barium..- lee Mod. I. 8!; L Cupric-.- L ht green needles L- Mod. I. Bl. I. NickeL... green thin plates. Ext. I. V. I. Silver.-.. White gins Bl. s. V. I1. I. Plumbous White e 81. s. V. II. I. Mercuric White diamond shape plates Bl. I. V. I1. I. Blsmuth..-. Whi needles V. sl. I. i. Aluminum White rods and medium... 81. I. V. I1. I. Ferric Li ht yellow (p h-n i. l. 13 123 1 315: niuln ihfl Mhguht O e a e Monc n-amyl ammonium Duelill" i Tetrahedral and spherical segments. 8. 81. I. Di-n-amyl ammonium Sod. Dsa.+ CIH|8INEH Feat 51. I. V. IL I. Triethanol ammonium--- Dsa.+(H0. HI. HQiN Not readily crystallisable syrup Ext. s. Ext. I.

1 In cold solution is precipitated as bronze scales which spontaneously change to the above.- Apparently quite light stable. in which it is very soluble. The free diiN-acetyl- I Exam 3 sulphanil) amide may be obtained by. acidifying m a m the sodium salt with a mineral acid. The free diamide is almost insoluble in dilute acids and s 0, =Nn melts with decomposition at 284-286 C. g

Instead of using N- acetylsulphanilylchlorlde NH: I

I is very soluble, preferably in the Exams: 2

Sodium disulphanilamidc The sodium di(N-acetylsulphanil)amlde described in Example 1 is hydrolyzed by 1 mol. of the crude paste with 6 mols of caustic soda in 200 parts of water until no further increase in diazotizable amine is noted. The hydrolysis mixtureis then cooled to 10' c. and the crude sodium disulphanilamide filtered on.

The crude product may be purified by recrystallization from hot water in which the compound of decolorizing carbon. The mother here may he treated with acid to produc '"a pH of 2 to 3 at which pH the free amide sh ws its minimum solubility. At body, temperature, the solubility of sodium disulphanilamide in water is 20 gs. per 100 cc. and at 10 0., this .has dropped to 9.6 gs. per 100 cc. The product melts with decompomtion to a characteristic bluecolorat temper- 1 mol of metanitrobenzenesulphonamide is dissolved in 1600 parts of water containing 16 parts of soda ash and 30 parts of caustic soda, the temperature being 45 C. 1.3 mols of metanitro bensenesulphonchloride are then added during one .half hour while maintaining apI-I of 10-11 by the addition of caustic soda solution as required. During reaction the temperature is maintained between 45 and 60? C. and after reaction is completastlrrlng is continued for 1 hour. The

cooling is provided, but as the reaction moderates,

the mixture is heated at a slow boil under a reflux condenser with continual passage of hydrogen sulphide for 1 hour. After reaction is substantially complete, air is passed through the hot solution to remove excess ammonia and to oxidize sulphides to sulphur. Thereupon the mixture is made alkaline to phenolphthalein with caustic soda and the sulphur filtered oif. Hydrochloric lbidllthenaddedtobrlnlthepfloftheclarmed melts with decomposition to EXAIPLI 4 Metanitrobenzenesulphonzrl(N-metanitrobenzenesulphonylsulphanil) amide Q-GOrNH-OSOs-NH-SOQ no, No,

1 mol of sulphanilamidej is suspended in 500 parts of water and 2 mols oi metanitrobenzenesulphonylchlorlde is gradually added with agita tion. A pH of 9 to 11 is maintained by the addition of 50% caustic soda as necessary, the temperature being kept at 40-50 C. by the addition of ice. After the addition is complete and the pH is adjusted, the reaction mixture is stirred for an hour and then strongly acidified and the precipitate of crude met-anitrobenzenesulphonyl(N-metanitrobenzenesulphonsulphanil) amide filtered oil.

NEQsomn-Os ol-i s-s Qr-O-Nm L1: 5 Sodium metaniKN-metanilylsulphanil) amide QMHOWHQ NH: NH:

The nitro compound produced in Example 4 is dissolved in 800 parts of strong ammonia and reduced by passing a rapid stream of hydrogen sulphide through it at first with cooling and then with the addition of heat to bring the reaction mixture near boiling. After passing hydrogen sulphide through for about 1 hours, air is passed through the reduction mixture to remove hydrogen sulphide and oxidize ammonium sulphide produced to sulphur. The sulphur is filtered ofifthe filtrate acidified and the crude product filtered off. Purification is effected by dissolving the crude product in a caustic soda solution, neutralized to a pH of 7, filtering ofl solid material, treating with decolorizing carbon and reprecipitating with acid. If desired, the purified product may be dissolved in a minimum amount of hot water, using caustic soda and adjusting to a pH of 7. On cooling, the sodium salt crystallizes out and can be further purified to complete whiteness by recrystallization from hot water. Titration by nitrite gives an equivalent weight of 251 as against a theoretical equivalent of 252.

Emu: 6 Tnsodium Di(N-sulphanil ylsalphanil) amide 2.2 mols of freshly prepared acetylsulphanilylchloride paste are introduced with agitation, a pH of 8 to being maintained by the addition of 50%- caustic soda solution as necessary. The temperature is maintained at 35-40 C. by external cooling and stirring at the same temperature is continued.

for2 hours after the addition 01' the acetylsulphanilylchloride is complete. The reaction mixture is then heated to 90 C., clarified andthe clarified liquid acidified with about 400 parts of concentrated hydrochloric acid. The precipitated salt is filtered oil and the filtrate discarded.

The paste is hydrolyzed by boiling for a half hour with 1200 parts of 18% hydrochloric acid after solution is complete. The reaction mixture is then neutralized with caustic soda to a pH of 4 to 5 and a tarry mass separates out. This is dissolved inaminimumamount of hot water containing sufflcient caustic soda solution to bring the pH up to 9 t'o 10. Decolorizing carbon is added to clarify, the mixture cooled and three volumes of" alcohol added. A crystalline product which precipitates out is filtered oil and washed with alcohol. Purification may be effected by repeated solution in small amounts of hot water and treatment with decolorizing carbon and precipitation with alcohol. The resulting product is'a mixture of the'diand tri-sodium salts and a nitrite titration shows a molecular weight of 698 which corre- Sodium sulphanil(N-sulphanilylsulphanil)- amide 1 mol otsulphanilamide is dissolved in 1000 parts of water at 35 C. with the addition of suificient caustic soda to bring the pH to 11. 2.4 mols of freshly prepared acetylsulphanilylchloride paste is then added during 20 minutes while maintaining a pH at 10 to 11 by the addition of 50% caustic soda solution as required. Sufilcient ice is added from time to time to maintain the temperature at 35-45 C. and stirring is continued for an hour after the addition is complete.

The product is hydrolyzed by adding 200 parts of caustic soda to the reaction-mixture and boilmg for two hours until there is no further increase in diazotizable amine. The hydrolysis mixture is neutralized to a pH of 7.5, cooled and the crude product crystallized out. Purification is effected by repeated recrystallizations from hot- Tltration by of 256 as against water using decolorizing carbon. nitrite gives a molecular weight 252 for theory.

If the free amide is desired, it may be protitration shows an equivalent weight of 243 as' against 241 for theory.

H Exam .8 v M ethyl di(N-acetylsulphanil) amide l-mol of sodium di(N-acetylsulphanil)amide is suspended in 2000 parts of dry'xylene and two mols of dimethyl sulphate added. The mixture is heated under a reflux condenser for three hours and the solid produced. filtered off, the filtrate being discarded. The solid is suspended in 3000 parts of water and warmed with the addition of 50% caustic soda solution until the solution is permanently alkaline to 'phenolphthalein. Insoluble material is filtered off and constitutes the crude methylated product. Unmethylated material can be recovered-by acidification of the filtrate and reprocessed. The crude material can be purified by dissolving in glacial acetic acid and precipitating by dilution with water. 0n heating, the product decomposes indefinitely above 210 C.

1 mol of acetylnaphthionamide is suspended in 1000 parts of water and the pH adjusted to 10 to 11 by the addition of caustic soda. 1.5 mols of paratoluenesulphonchloride is added over a period of 2 hours while maintaining the reaction mixture at 60-65 0., strong caustic soda solution being added to maintain the pH between 9 and 10. The mixture is then neutralized to pH of 7 .5 and clarified with decolorizing carbon. After clarification, the solution is made acid to Congo with hydrochloric acid and the precipitate iiitered off. This is crude paratoluenesulphonylacetylnaphthionamide.

The product is hydrolyzed by dissolving in 1000 parts of water containing three mols of caustic soda and boiling for 2% hours. The hydrolysis mixture is acidified until it turns Congo red and is cooled, the crude product being filtered ofi. Purification is effected by recrystallization from dioxane using decolorizi'ng carbon. The compound melts with decomposition at 156-15'1 C. What I claim is:

1. Disulphonamides having the following formula:

x iv-s o,

in which R is an aminoaryl radical, R is a mononuclear aryl radical and X is a member of the group consisting of hydrogen, a metal, an alkyl 45 radical and an aryl radical.

2. Diiaminoarylsulphon) amides having the following general formula:

R-SOI in ,which R is an aminoaryl radical, R is a mononuclear aryl radical containing at least one amino group or substituted amino group and x 55 is a member of the group consisting of hydrogen, a metal, an alkyl radical and an aryl radical.

3. Di(amino arylsulphon) amides having the following formula: nrm s .N

in which R is hydrogen, an acyl or an aminoaryl 06 sulphonyl radical, R is an aminoaryl radical and x is a member of the group consisting of hydrogen, a metal, an alkyl radical and an aryl radical.

a satev 4. Disulphanilamides having the following formula: 4

in which x is a member of the group consisting of hydrogen, a metal, an alkyl radical and an aryl radical.

6. Disulphanilamides having the following formula:

in which X is a metal forming a water-soluble salt of disulphanilamide.

8. A method of producing a di(aminoarylsul- I phon) amide which comprises reacting an acetylaminoarylsulphonchloride wi an acetylaminoarylsulphonamide and hydr yzing the acetylamino group.

9. A method of preparing a di(aminoarylsulaminosulphonchloride with ammonia, at least two mols of the acetylaminoarylsulphonchloride being prgsentfor each mol. of ammonia and hydrolyzing th acetylamino group.

10. A method of preparing a di(aminoarylsulphon) amide. which comprises reacting a nitrophon) amide which comprises reacting an acetylarylsulphonchloride with a compound included in the group consisting of acetylaminoarylsulphonamides and nitroarylsulphonamides, reducing all nitro groups to amino groups and hydrolyzing any acetylamino group present.

11. Disulphonamides "according to claim 1 in which X is a heavy metal.

12. Di(aminoarylsulphon) amides according to claim 2 in which X is a heavy metal.

13. Disulphanilamides according to claim 6 in which X is a heavy metal ELMORE HATHAWAY NORTHEY. 

